Heteroannelated anthraquinone derivatives and the synthesis method thereof

ABSTRACT

A heteroannelated anthraquinone derivative compound is provided. The heteroannelated anthraquinone derivative compound is represented by a formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R 1  is a substituent being one selected from a group consisting of i) a first substituent being one selected from a group consisting of a hydryl group, an amino group, a nitro group, a hydroxyl group and a cyan group, ii) a second substituent being one selected from a group consisting of (CH 2 ) n X, a straight (CH 2 ) n  alkyl group, a (CH 2 ) n  alkoxyl group, a branched (CH 2 ) n  alkyl group, a C 3 ˜C 12 nephthenic group, and a C 3 ˜C 12  cyclic alkoxyl group, wherein 1=n=12, and X is a halogen, iii) a third substituent being one selected from a group consisting of a straight C 1 ˜C 8  alkyl group with a double-bond, a C 1 ˜C 8  alkoxyl group with a double-bond, a branched C 1 ˜C 8  alkyl group with a double-bond and a C 3 ˜C 8  nephthenic group with a double-bond, and iv) a fourth substituent of a C 5 ˜C 12  heterocyclic group.

FIELD OF THE INVENTION

The present invention relates to heteroannelated anthraquinonederivatives for inhibiting a proliferation activity of a cancer cell,and more particularly to a series of heteroannelated anthraquinonederivatives and the synthesis method thereof.

BACKGROUND OF THE INVENTION

In normal somatic cells, the telomere, which is located at the end of achromosome, gets shortened at each time of cell mitosis. When thetelomere is shortened to some level, the cell will lose the ability ofreplication and go into apoptosis stage. Telomerase, which is aribonucleoprotein, acts on the telomere in a eukaryocyte, so as toprolong or maintain the length of the telomere. A telomerase mainlyincludes two portions; one is a protein sub-unit with activity ofreverse transcription, i.e. the human telomerase reverse transcriptase(hTERT), and the other one is an RNA template for synthesizing repeatedsequences of the telomerase, i.e. the human telomerase RNA component(hTR), wherein the RNA template includes the single RNA sequence,-AAUCCC, which is complementary to the telomerase sequence. Telomeraseactivity is rarely detected in normal human somatic cells, but isusually detected in the cells that keep proliferating, such ashematopoietic cells, embryogenic cells, stem cells, etc. It is estimatedthat about 85-90% of human tumor cells have telomerase activity, andthat is the reason why tumor cells do not go into apoptosis like anormal cell and can keep proliferating (Urquidi et al., Annu. Rev. Med.2000, 51, 65-79). Reductions in hTERT mRNA expression level andtelomerase activity are observed during the processes of cell going agedor immortalized (Bestilny et al., Cancer Res. 1996, 56, 3796-802).Furthermore, the telomerase activity of a somatic cell that should notexpress the telomerase activity could be reproduced by introduction ofthe hTERT cDNA thereinto for a high level expression of telomeraseactivity (Bodnar et al., Science. 1998, 279, 349-52).

The telomere at chromosome ends of eukaryotic cells is guanine-rich. Innormal physiological conditions, the single strand DNA of the telomerespontaneously forms a G-quadruplex structure. The G-quadruplex structureincludes two portions, wherein one is a small loop composed of TTA, andthe other one is a guanine-tetrad composed of four guanines formed bycyclic hydrogen bonds. In order to inhibit the differentiation of tumorcells, an alternative besides the direct inhibition to telomeraseactivity is to stabilize the G-quadruplex structure for inhibiting itsreaction with the complementary single strand RNA (AAUCCC), so as toprevent the telomerase from extending the telomere. Chromosomereplications of tumor cells may be inhibited by the mentioned method, soas to achieve the anti-caner effect directly or indirectly (Smogorzewskaet al., Annu. Rev. Biochem. 2004, 73, 177-208).

It is observed in current studies that anthraquinone can stabilize theG-quadruplex structure for its formula with plane tri-cyclic structure.According to the researches to the quindoline derivatives(10H-indolo[3,2-b]quinoline) with tetra-cyclic structure, berberin withnon-plane polycyclic structure and the analogs synthesized therefrom, itis known that the aromatic groups of the mentioned compounds play animportant role in the bonding to the G-quardruplex structure.Over-expressions of known oncogenes usually induce cancers and areassociated with many cell proliferation disorders, such as chroniclymphocytic leukemia, esophagus cancer, myeloma, etc. In additions,those genes also participate in many pathological and physiologicalprocesses. Many experiments have proved that over-expressions of tumorsuppressor genes play important role in the prevention and treatment oftumors. Therefore, the research and development of the drugs for curingcell proliferation disorders can be applied in the cure of humancancers, just like the disclosures of Canadian Patent No. 2,428,206.

Although it has been published that a heteroannelated anthraquinonederivative can be synthesized by an acylation reaction of1,2-diaminoanthraquinone to obtain a bis-substituent derivative,followed by a consensation reaction. However, this method only disclosesthe substituent of aromatic groups, and has a poor production rate (Penget al., J. Org. Chem. 2005, 70, 10524-31).

Based on the above, the present invention provides heteroannelatedanthraquinone derivatives and the synthesis method thereof, which isaccomplished by preserving the chromophore group with plane tri-cyclicstructure and the carbonyl groups at 9 and 10, which have better bindingability, then changing the tri-cyclic structure into tetra-cyclicstructure and adding various side chains derived from different modifiedsubstituents, so as to synthesize a series of heteroannelatedanthraquinone derivatives.

SUMMARY OF THE INVENTION

The present invention provides a series of heteroannelated anthraquinonederivatives for inhibiting the proliferation activity of cancer cells,which facilitate the study and application regarding cancer cells.

In accordance with the first aspect of the present invention, aheteroannelated anthraquinone derivative compound is provided. Thecompound is represented by a formula (I):

wherein R₁ is a substituent being one selected from a group consistingof i) a first substituent being one selected from a group consisting ofa hydryl group, an amino group, a nitro group, a hydroxyl group and acyan group, ii) a second substituent being one selected from a groupconsisting of (CH₂)_(n)X, a straight (CH₂)_(n) alkyl group, a (CH₂)_(n)alkoxyl group, a branched (CH₂)_(n) alkyl group, a C₃˜C₁₂nephthenicgroup, and a C₃˜C₁₂ cyclic alkoxyl group, wherein 1=n=12, and X is ahalogen, iii) a third substituent being one selected from a groupconsisting of a straight C₁˜C₈ alkyl group with a double-bond, a C₁˜C₈alkoxyl group with a double-bond, a branched C₁˜C₈ alkyl group with adouble-bond and a C₃˜C₈ nephthenic group with a double-bond, and iv) afourth substituent of a C₅˜C₁₂ heterocyclic group, wherein one of thenephthenic group and the heterocyclic group further has at least one ofan ortho-substitution, a meta-substitution and a para-substitution, andcomprises at least a fifth substituent for any of the substitutionsbeing one selected from a group consisting of an alkyl group with aC₁˜-C₃ substituent branch, an amino group, a nitro group, a hydroxylgroup and a cyan group, a C₁˜C₅ alkyl group, a halogen substituted C₁˜C₅alkyl group, a C₁˜C₅ alkoxyl group, a halogen substituted C₁˜C₅ alkoxylgroup, a C₁˜C₅ cyclic alkoxyl group, and a halogen substituted C₁˜C₅cyclic alkoxyl group.

Preferably, the halogen is one selected from a group consisting of afluorine, a chlorine, a bromine and an iodine.

Preferably, the second substituent is one selected from a groupconsisting of a methyl group, an ethyl group, a propyl group, a butylgroup, an isobutyl group, a pentyl group, an isopentyl group, acyclopentyl group, a heptyl group, an isoheptyl group, a cycloheptylgroup, an octyl group, an isooctyl group, a cyclooctyl group, a straightalkyl group with a branch substituted by a straight C₁˜C₅ alkyl group, anephthenic group with a branch substituted by a straight C₁˜C₅ alkylgroup, alkoxyl derivatives of the mentioned alkyl groups, andhalogenated derivatives of the mentioned alkyl groups.

Preferably, the third substituent is one selected from a groupconsisting of a vinyl group, a propenyl group, a butenyl group, anisobutenyl group, a pentenyl group, an isopentenyl group, acyclopentenyl group, a hexenyl group, a cyclohexenyl group, a heptenylgroup, an cycloheptenyl group, a straight alkyl group with a branchsubstituted by a straight C₁˜C₃ alkyl group, a nephthenic group with abranch substituted by a straight C₁˜C₃ alkyl group, alkoxyl derivativesof the mentioned groups, and halogenated derivatives of the mentionedgroups.

Preferably, the heteroannelated anthraquinone derivative compound isused as an effective component together with an excipient to provide apharmaceutic composition for inhibiting one selected from a groupconsisting of a growth of a cancer cell, a disease of cellproliferation, and a growth of cell telomere.

In accordance with the second aspect of the present invention, aheteroannelated anthraquinone derivative compound is provided. Thecompound is represented by a formula (II):

Preferably, the heteroannelated anthraquinone derivative compound isused as an effective component together with an excipient to provide apharmaceutic composition for inhibiting one selected from a groupconsisting of a growth of a cancer cell, a disease of cellproliferation, and a growth of cell telomere.

In accordance with the third aspect of the present invention, aheteroannelated anthraquinone derivative compound is provided. Thecompound is represented by a formula (III):

wherein either one of R₂ and R₃ is one of i) a first substituent beingone of a hydryl group and a sulfuryl-group, and ii) a second substituentbeing one selected from a group consisting of a C₁˜C₈ alkyl group, aC₁˜C₈ alkoxyl group, a C₃˜C₈ nephthenic group, and a C₃˜C₈ cyclicalkoxyl group, a straight alkyl group with a branch substitutent, anephthenic group with a branch substitutent by a straight C₁˜C₅ alkylgroup and halogenated derivatives of the mentioned substitent groups.

Preferably, the second substituent is one selected from a groupconsisting of a methyl group, an ethyl group, a propyl group, a butylgroup, an isobutyl group, a pentyl group, an isopentyl group, acyclopentyl group, a heptyl group, an isoheptyl group, a cycloheptylgroup, an octyl group, an isooctyl group, a cyclooctyl group, a phenylgroup, a benzyl group, a phenethyl group, a straight alkyl group with abranch substituted by a straight C₁˜C₃ alkyl group, a nephthenic groupwith a branch substituted by a straight C₁˜C₃ alkyl group, alkoxylderivatives of the mentioned substituent groups, and halogenatedderivatives of the mentioned substituent groups.

Preferably, the heteroannelated anthraquinone derivative is used as aneffective component together with an excipient to provide a pharmaceuticcomposition for inhibiting one selected from a group consisting of agrowth of a cancer cell, a disease of cell proliferation, and a growthof cell telomere.

In accordance with the fourth aspect of the present invention, aheteroannelated anthraquinone derivative compound is provided. Thecompound is represented by a formula (IV):

wherein R₄ is one selected from a group consisting of a hydryl group, aC₁˜C₄ alkyl group, a C₁˜C₄ alkoxyl group, a C₁˜C₄ ketone group, astraight alkyl group with a branch substituted by a straight C₁˜C₃ alkylgroup, a halogen substituted C₁˜C₄ alkyl group, and a C₁˜C₄ alkoxylgroup.

Preferably, A compound as claimed in claim 12, being used as aneffective component together with an excipient to provide a pharmaceuticcomposition for inhibiting one selected from a group consisting of agrowth of a cancer cell, a disease of cell proliferation, and a growthof cell telomere.

In accordance with the fifth aspect of the present invention, a methodfor manufacturing a compound having the formula (I) is provided. Themethod includes steps of a) dissolving a diaminoanthraquinone in adimethylformamide solution for forming a solution A, b)adding anddissolving a chloroacetyl chloride in the solution A for forming asolution B, c) mixing and reacting the solution B by a reverse flowmethod, and then transferring the solution B into an icy water forforming a solution C, d) filtering the solution C for obtaining aprecipitate, and e) washing the precipitate by using an ethanol forobtaining the compound of the formula (I).

In accordance with the sixth aspect of the present invention, a methodfor manufacturing a compound having the formula (I) is provided. Themethod includes steps of a) dissolving a diaminoanthraquinone in adimethylformamide solution for forming a solution A, b) adding anddissolving a reagent in the solution A for forming a solution B, whereinthe reagent is one of a benzaldehyde and a carbon disulfide, c)catalyzing a reaction of the solution B by adding a concentratedsulfuric acid thereinto, and then transferring the solution B into anice water for forming a solution C, d) filtering the solution C forobtaining a precipitate, and e) washing the precipitate by using anethanol for obtaining the compound of the formula (I), wherein when thereagent is the carbon disulfide, a triethylamine is further added intothe solution B before the step c).

In accordance with the seventh aspect of the present invention, a methodfor manufacturing a compound having the formula (III) is provided. Themethod includes steps of a) dissolving a diaminoanthraquinone in anacetone for forming a solution A, b) adding a concentrated sulfuric acidinto the solution A for forming a solution B, c) transferring thesolution B into a potassium carbonate column for obtaining a solution C,and d) using a methanol to crystallize the compound of the formula (III)in the solution C.

Preferably, the step b) is performed in a room temperature.

In accordance with the eighth aspect of the present invention, a methodfor manufacturing a compound having the formula (IV) is provided. Themethod includes steps of a) dissolving a diaminoanthraquinone in adimethylformamide solution for forming a solution A, b) adding a glyoxalethanol solution into the solution A for forming a solution B, c)reacting the solution B by a reverse flow reaction, d) filtering thesolution B for obtaining a precipitate, and e) washing the precipitateby using a hot alcohol and a dichloromethane for separating out thecompound of the formula (IV).

Alternatively, in some steps of the above-mentioned methods, theproduction rate will increase if the solvents used for dissolving thediaminoanthraquinone contain less water. In the purification steps forthe products, alcohol could be used for crystallization; alternatively,hot alcohol could be used for washing the products. The products withhigh solubility could be dissolved in alcohol before crystallization.The products with low solubility need to be washed by hot alcohol towash out initial material or impurities and by-products generated in thereaction. Compared with recrystallization, although parts of productswould be lost in the washing steps, it would be easier to obtain thepurified products.

The compound provided in the present invention could be supplied withexcipients, carriers or diluent, such starch or binder likecarboxymethyl cellulose (CMC), so as to prepare granulated pill, tablet,or capsule. Alternatively, the compound could be dissolved in phosphatebuffer for adjusting the pH thereof, so as to prepare injection. Thecompound could be supplied with penetration enhancer, so as to prepareabsorbate by skin.

Additional objects and advantages of the invention will be set forth inthe following descriptions.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention will now be described more specifically with theexperiment results of the following embodiments. It is to be noted thatthe following descriptions of preferred embodiments of this inventionare presented herein for the purposes of illustration and descriptiononly; it is not intended to be exhaustive or to be limited to theprecise form disclosed.

Concretely speaking, the method for manufacturing the heteroannelatedanthraquinone derivative includes cyclization and condensationreactions.

Embodiment 1 (2-Methyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 2)

1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in 30 mL ofN,N-dimethylformamide, and chloroacetyl chloride (0.5 mL, 6 mmol) isadded thereinto. After ten hours of mixing and reacting by a reverseflow, the mixture is transferred into 200 mL of icy water. Afterfiltering, the precipitate is collected and washed by hot alcohol, so asto obtain the black compound No. 2.

The compound No. 2 has the following characterstics: MW 262.0724(C₁₆H₉N₂O₂); R_(f): 0.79 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 1667 (CO); EI-MS m/z: 262 (M⁺, 100%); ¹H-NMR (300 MHz, DMSO-d₆) d(ppm): 2.72 (3H, s,—CH₃), 7.75-7.82 (2H, m, Ar—H_(7,10)), 7.93 (1H, d,J=8.4 Hz, Ar—H₅), 8.13 (1H, d, J=8.4 Hz, Ar—H₄), 8.19-8.23 (1H, m,Ar—H8,9), 11.01 (1H, br, —NH); and ¹³C-NMR (75 MHz, DMSO-d6) d (ppm):23.89, 120.23, 121.22, 125.29, 126.19, 126.75, 127.19, 128.17, 128.87,132.98, 134.18, 134.42, 148.22, 158.09, 182.43 (CO), 185.13 (CO).

Embodiment 2 (2-Chloroacetyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione,No. 3)

Except controlling the reacting temperature in 50-60° C., all steps areidentical with the steps for manufacturing the compound No. 2, and theyellowish brown compound No. 3 can be obtained.

The compound No. 3 has the following characterstics: MW 296.0353(C₁₆H₉N₂O₂Cl); R_(f): 0.5 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 3359(NH), 1660 (CO); HRMS (ESI-TOF) m/z: calcd for C₁₆H₁₀N₂O₂Cl⁺[M+H]⁺: 297.0425, found: 297.0426; ¹H-NMR (300 MHz, CDCl₃) d (ppm): 4.92(2H, s, —CH₂Cl), 7.80-7.83 (2H, m, Ar—H_(7,10)), 8.08 (1H, d, J=8.4 Hz,Ar—H₅), 8.24(1H, d, J=8.4 Hz, Ar—H₄), d8.26-8.35(2H, m, Ar—H_(8,9)),d11.21(1H, br, —NH); and ¹³C-NMR (75 MHz, DMSO) d (ppm): 37.80, 119.35,121.27, 125.95, 126.83, 127.40, 129.06, 132.35, 133.47, 133.64, 134.88,135.10, 148.89, 156.93, 183.04 (CO), 183.83 (CO).

Embodiment 3 (2-Ethyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 4)

1,2-Diaminoanthraquinone (1.19 g, 5 mmol) was dissolved indimethylformamide (30 mL), and propionaldehyde (0.29 g, 5 mmol) is addedthereinto. Concentrated sulfuric acid (0.1 mL) is added thereinto forcatalyzation. After mixing and reacting at room temperature for onehour, the reacted mixture is transferred into 200 mL of icy water and isextracted by using dichloromethane. The extract is dried, andcrystallized by using alcholo, so as to obtain the brown compound No. 4.

The compound No. 4 has the following characterstics: MW 276.0899(C₁₇H₁₂N₂O₂); R_(f): 0.75 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 1669 (CO); HRMS (ESI-TOF) m/z: calcd for C₁₇H₁₃N₂O₂ ⁺ [M+H]⁺:277.0971, found: 277.0975 calcd for C₁₇H₁₂N₂O₂Na⁺ [M+Na]⁺: 299.0971,found: 299.0794; ¹H-NMR (300 MHz, CDCl₃) d (ppm): 1.51 (3H, t, J=7.5 Hz,—CH₃), 3.05 (2H, q, J=7.5 Hz, —CH₂—), 7.73-7.81 (2H, m, Ar—H_(7,10)),7.99 (1H, d, J=8.4 Hz, Ar—H₅), d8.16(1H, d, J=8.4 Hz, Ar—H₄),d8.21-8.23(1H, m, Ar—H₉), d8.27-8.31(1H, m, Ar—H₈), d10.85(1H, br, —NH);and ¹³C-NMR (75 MHz, CDCl₃) d (ppm): 11.87, 22.89, 117.74, 121.50,125.21, 126.47, 127.55, 128.21, 132.72, 133.24, 133.72, 133.99, 134.37,148.90, 161.64, 182.81 (CO), 185.15 (CO).

Embodiment 4 (2-Isopropyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No.5)

All steps for manufacturing the yellow compound No. 5 are identical withthe steps of Embodiment 3, except that propionaldehyde is substituted byisobutyraldehyde (0.41 g, 5 mmol).

The compound No. 5 has the following characterstics: MW 290.1055(C₁₈H₁₄N₂O₂); R_(f): 0.7 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 3445 (NH), 1662 (CO); HRMS (ESI-TOF) m/z: calcd for C₁₈H₁₅N₂O₂ ⁺[M+H]⁺: 291.1120, found: 291.1123; ¹H-NMR (300 MHz, CDCl₃) d (ppm):d1.56(6H, d, J=6.6 Hz, —CH₃), d3.40(1H, sp, J=6.6 Hz, —CH—),d7.78-7.85(2H, m, Ar—H_(7,10)), d8.11(1H, d, J=8.4 Hz, Ar—H₅), d8.23(1H,d, J=8.4 Hz, Ar—H₄), d8.25-8.36(2H, m, Ar—H_(8,9)), d10.88(1H, s, —NH);and ¹³C-NMR (75 MHz, CDCl₃) d (ppm): 21.15, 29.21, 117.66, 121.36,125.21, 126.32, 127.42, 128.05, 132.49, 133.10, 133.61, 133.86, 134.24,148.71, 165.35, 181.05(CO), 182.73(CO).

Embodiment 5 (2-Butyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 6)

All steps for manufacturing the brown compound No. 6 are identical withthe steps of Embodiment 3, except that propionaldehyde is substituted bypentanal (0.45 g, 5 mmol).

The compound No. 6 has the following characterstics: MW 304.1212(C₁₉H₁₆N₂O₂); R_(f): 0.65 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 1669 (CO); HRMS (ESI-TOF) m/z: calcd for C₁₉H₁₇N₂O₂ ⁺ [M+H]⁺:305.1276, found: 305.1282 calcd for C₁₉H₁₅N₂O₂ ⁻ [M-H]⁻: 303.1131,found: 303.1135; ¹H-NMR (300 MHz, CDCl₃) d (ppm): d1.00(3H, t, J=7.2 Hz,—CH₃), d1.50(2H, sx, J=7.5 Hz, —CH₂—), d1.93(2H, qt, J=7.8 Hz —CH₂—),d3.04(2H, t, J=7.5 Hz, —CH₂—), d7.62-7.83(2H, m, Ar—H_(7,10)), d8.03(1H,d, J=8.4 Hz, Ar—H₅), d8.20, 1H, d, J=8.1 Hz, Ar—H₄), d8.24-8.35(2H, m,Ar—H_(8,9)) d10.83(1H, s, —NH); and ¹³C-NMR (75 MHz, CDCl₃) d (ppm):12.98, 21.78, 28.60, 29.27, 117.32, 121.07, 124.64, 125.98, 127.08,127.83, 132.17, 132.84, 133.20, 133.61, 133.86, 148.25, 160.29,182.31(CO), 184.78(CO).

Embodiment 6 (2-sec-Butyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No.7)

All steps for manufacturing the yellow compound No. 7 are identical withthe steps of Embodiment 3, except that propionaldehyde is substituted bymethylbutyraldehyde (0.46 g, 5 mmol).

The compound No. 7 has the following characterstics: MW 304.1212(C₁₉H₁₆N₂O₂); R_(f): 0.57 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 1665 (CO); HRMS (ESI-TOF) m/z: calcd for C₁₉H₁₇N₂O₂ ⁺ [M+H]⁺:305.1276, found: 305.1280 calcd for C₁₉H₁₅N₂O₂ ⁻ [M−H]⁻: 303.1131,found: 303.1137; ¹H-NMR (300 MHz, CDCl₃) d (ppm): d1.00(3H, t, J=7.2 Hz,—CH₃), d1.52(3H, d, J=6.9 Hz , —CH₃), d1.82-2.02(2H, m, —CH₂—),d3.04(1H, sx, J=7.2 Hz, —CH—), d7.62-7.83(2H, m, Ar—H_(7,10)), d8.03(1H,d, J=8.4 Hz, Ar—H₅), d8.20(1H, d, J=8.1 Hz, Ar—H₄), d8.24-8.35(2H, m,Ar—H_(8,9)), d10.83(1H, s, —NH); and ¹³C-NMR (75 MHz, CDCl₃) d (ppm):11.09, 18.09, 28.40, 35.71, 117.39, 121.07, 124.75, 125.95, 127.09,127.84, 131.92, 132.83, 133.22, 133.59, 133.87, 148.06, 164.30,182.31(CO), 184.82(CO).

Embodiment 7 (2-tert-Butyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No.8)

All steps for manufacturing the yellow compound No. 8 are identical withthe steps of Embodiment 3, except that propionaldehyde is substituted bytrimethylacetaldehyde (0.46 g, 5 mmol).

The compound No. 8 has the following characterstics: MW 304.1212(C₁₉H₁₆N₂O₂); R_(f): 0.8 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 3568(NH), 1664 (CO); HRMS (ESI-TOF) m/z: calcd for C₁₉H₁₇N₂O₂ ⁺[M+H]⁺: 305.1276, found: 305.1283 calcd for C₁₉H₁₅N₂O₂ ⁻ [M−H]⁻:303.1131, found: 303.1136; ¹H-NMR (300 MHz, CDCl₃) d (ppm): d1.58 (9H,s, —C(CH₃)₃), d7.77-7.84 (2H, m, Ar—H_(7,10)), d8.08 (1H, d, J=8.4 Hz,Ar—H₅), d8.21 (1H, d, J=8.4 Hz, Ar—H₄), d8.25-8.28 (1H, m, Ar—H₈),d8.33-8.36 (1H, m, Ar—H₉), d10.83 (1H, s, —NH); and ¹³C-NMR (75 MHz,CDCl₃) d (ppm): 29.24, 117.79, 121.47, 125.41, 126.39, 127.56, 128.17,132.70, 133.23, 133.74, 133.96, 134.37, 148.73, 168.00, 182.77(CO),185.26(CO).

Embodiment 8 (2-Heptyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 9)

All steps for manufacturing the brown compound No. 9 are identical withthe steps of Embodiment 3, except that propionaldehyde is substituted byoctanal (0.29 g, 5 mmol).

The compound No. 9 has the following characterstics: MW 346.1681(C₂₂H₂₂N₂O₂); R_(f): 0.85 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 3447(NH), 1664 (CO); HRMS (ESI-TOF) m/z: calcd for C₂₂H₂₃N₂O₂ ⁺[M+H]⁺: 347.1754, found: 347.1752; ¹H-NMR (300 MHz, CDCl₃)d (ppm):d0.87-0.91 (3H, m, —CH₃), d1.26-1.35(6H, m, —CH₂—), d1.56(2H, sx, J=7.0Hz, —CH₂—), d2.36(2H, q, J=7.0 Hz, —CH₂—), d2.71(2H, t, J=7.0 Hz,—CH₂—),d7.75-7.81 (2H, m, Ar—H_(7,10)), d8.04 (1H, d, J=8.0 Hz, Ar—H₅),d8.17 (1H, d, J=8.0 Hz, Ar—H₄), d8.23-8.25 (1H, m, Ar—H₈), d8.31-8.33(1H, m, Ar—H₉), d10.93 (1H, s, —NH); and ¹³C-NMR (75 MHz, CDCl₃) d(ppm): 14.08, 22.63, 27.99, 28.79, 29.24, 29.46, 31.79, 117.49, 121.66,125.28, 126.37, 127.54, 130.56, 133.27, 133.67, 134.06, 134.31, 137.37,149.40, 158.89, 182.69(CO), 185.25(CO).

Embodiment 9((E)-2-(But-1-enyl)-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 10)

All steps for manufacturing the brown compound No. 10 are identical withthe steps of Embodiment 3, except that propionaldehyde is substituted bytrans-2-pentenal (0.46 g, 5 mmol).

The compound No. 10 has the following characterstics: MW 302.1055(C₁₉H₁₅N₂O₂); R_(f): 0.57 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 1664 (CO); EI-MS m/z: 302 (M⁺, 100%); ¹H-NMR (300 MHz, CDCl₃) d(ppm): d0.98(3H, t, J=6.9 Hz, —CH₃), d1.94-1.98(2H, m, —CH₂—),d6.16-6.29(1H, m, —CH—), d6.51(1H, d, J=18 Hz, —CH—), d7.68(1H, d, J=8.4Hz, Ar—H₅), d7.82-7.89(2H, m, Ar—H_(7,10)), d8.14(1H, d, J=8.1 Hz,Ar—H₄), d8.27-8.35(2H, m, Ar—H_(8,9)), d10.74(1H, s, —NH); and ¹³C-NMR(75 MHz, CDCl₃) d(ppm): 14.39, 27.40, 117.37, 120.03, 121.07, 124.75,125.95, 127.09, 127.84, 131.92, 132.83, 133.22, 133.59, 133.87, 134.90,135.37, 149.06, 182.73(CO), 185.18(CO).

Embodiment 10 (2-Mercapto-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No.23)

1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved inN,N-dimethylformamide (30 mL), and triethylamine (3 mL) is further addedthereinto after carbon disulfide (0.4 g, 5 mmol) is added thereinto.After mixing in room temperature and performing reverse flow for tenhours, the reacted mixture is transferred into 200 mL of icy water.After filtering, the precipitate is collected and washed by hotalcolhol, so as to obtain reddle compound No. 23 with melting point of407-409° C., and the production rate is 80%.

The compound No. 23 has the following characterstics: MW 280.0306(C₁₅H₈N₂O₂S); R_(f): 0.80 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 3221(NH), 3192(NH), 1665(CO); HRMS (ESI-TOF) m/z: calcd forC₁₅H₉N₂O₂S⁺ [M+H]⁺: 281.0379, found: 281.0389; ¹H-NMR (300 MHz, DMSO-d₆)d (ppm): d7.54(1H, d, J=8.1 Hz, Ar—H₅), d8.02 (1H, d, J=8.1 Hz, Ar—H₄),d7.91-7.94 (2H, m, Ar—H_(7,10)), d8.18-8.22 (2H, m, Ar—H_(8,9)), d12.73(1H, s, —NH), d13.29 (1H, s, —NH); and ¹³C-NMR (75 MHz, DMSO-d₆) d(ppm): 113.89, 115.27, 122.41, 126.26, 126.76, 126.88, 130.95, 132.89,133.06, 134.25, 134.47, 138.19, 172.89, 181.79(CO), 182.46(CO).

Embodiment 11 (2-Phenyl-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 11)

1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved indimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL) isfurther added thereinto for catalyzation after benzaldehyde (0.6 mL, 5mmol) is added thereinto. After mixing and reacting in room temperaturefor one hour, the reacted mixture is transferred into 200 mL of icywater. After filtering, the precipitate is collected and washed by hotalcolhol, so as to obtain yellowish brown compound No. 11.

The compound No. 11 has the following characterstics: MW 324.0899(C₂₁H₁₂N₂O₂); R_(f): 0.55 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 3296(NH), 1660 (CO); EI-MS m/z: 324(M⁺, 100.00%), 325(19%); HRMS(ESI-TOF) m/z: calcd for C₂₁H₁₃N₂O₂ ⁺ [M+H]⁺: 325.0971, found: 325.0973;¹H-NMR (300 MHz, DMSO-d₆) d (ppm): d7.57(3H, t, J=3 Hz, Ar′—H_(3,4,5)),d7.89(2H, m, Ar—H_(7,10)), d8.03(1H, d, J=8.4 Hz, Ar—H₅), d8.08(1H, d,J=8.4 Hz, Ar—H₄), d8.16(2H, m, Ar—H_(8,9)), d8.40(2H, dd, J=6,3 Hz,Ar′—H_(2,6)); and ¹³C-NMR (75 MHz, DMSO-d₆) d (ppm): 119.62, 121.72,125.06, 126.85, 127.42, 128,79, 128.86, 129.41, 129.50, 131.72, 133.72,133.77, 134.92, 135.07, 149.26, 158.25, 183.06(CO), 183.79(CO).

Embodiment 12 (2-(4-N,N-Dimethylamino)phenyl-(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 12)

All steps for manufacturing the deep brown compound No. 12 are identicalwith the steps of Embodiment 11, except that benzaldehyde is substitutedby 4-dimethylaminobenzaldehyde (0.77 g, 5 mmol).

The compound No. 12 has the following characterstics: MW 367.1321(C₂₃H₁₇N₃O₂); R_(f): 0.6 (ethyl acetate: dichloromethane=1:4);IR(KBr)cm⁻¹: 3404(NH), 1659(CO); EI-MS m/z: 366(27%), 367(M⁺, 100.00%),368(20%); HRMS (ESI-TOF) m/z: calcd for C₂₃H₁₈N₃O₂ ⁺ [M+H]⁺: 368.1393,found: 368.1393; ¹H-NMR (300 MHz, CDCl₃) d (ppm): d3.09 (6H, s,—N(CH₃)₂), d6.81 (2H, d, Ar—H), d7.79˜7.82 (3H, m, Ar—H), d8.03-8.22(3H, m, Ar—H), d8.27˜8.36 (2H, m, Ar—H), d11.10 (1H, br, —NH); and¹³C-NMR (75 MHz, CDCl₃) d (ppm): 39.95, 111.65, 115.23, 117.13, 121.83,124.24, 126.33, 127.37, 127.44, 128.27, 133.27, 133.45, 133.54, 134.12,150.11, 152.10, 157.59, 182.47(CO), 185.09(CO).

Embodiment 13(2-(4-Nitrophenyl)-1(3)H-anthra[1,2-d]imidazole-6,11-dione, No. 13)

All steps for manufacturing the deep brown compound No. 13 are identicalwith the steps of Embodiment 11, except that benzaldehyde is substitutedby 4-nitrobenzaldehyde (0.78 g, 5 mmol).

The compound No. 13 has the following characterstics: MW 369.0750(C₂₁H₁₁N₃O₄); R_(f): 0.6 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 3460(NH), 1657(CO), 1517, 1345(NO₂); EI-MS m/z: 249(100%), 369(M⁺,35%); HRMS (ESI-TOF) m/z: calcd for C₂₁H₁₂N₃O₄ ⁺ [M+H]⁺: 370.0822,found: 370.0823; ¹H-NMR (300 MHz, DMSO-d₆) d (ppm): d7.79-7.82 (3H, m,Ar—H_(7,10)), d7.14 (1H, d, J=8.1 Hz, Ar—H₄), d8.23 (1H, d, J=8.1 Hz,Ar—H₅), d8.23-8.32 (2H, m, Ar—H_(8,9)), d8.39 (2H, d, J=8.1 Hz,Ar′—H_(2,6)), d8.58 (2H, d, J=8.1 Hz, Ar′—H_(3,5)), d10.15 (1H, br,—NH); and ¹³C-NMR (75 MHz, DMSO-d₆) d (ppm): 117.81, 122.43, 123.62,125.24, 125.88, 126.10, 127.92, 133.22, 133.36, 134.53, 143.08, 146.39,146.77, 155.89, 172.18, 178.35, 179.40, 183.20(CO), 185.56(CO).

Embodiment 14(2-(4-Hydroxy-3-methoxyphenyl)-1H-anthra[1,2-d]imidazole-6,11-dione, No.14)

1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved indimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL) isfurther added thereinto for catalyzation after vanillin (0.77 g, 5 mmol)is added thereinto. After mixing and reacting in room temperature forone hour, the reacted mixture is transferred into 200 mL of icy water.After filtering, the precipitate is collected and washed by hotalcolhol, so as to obtain brown compound No. 14.

The compound No. 14 has the following characterstics: MW 370.0954(C₂₂H₁₄N₂O₄); R_(f): 0.2 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 3411(OH), 3411(NH), 1664(CO); EI-MS m/z: 369(57%), 370(M⁺, 100%)HRMS (ESI-TOF) m/z: calcd for C₂₂H₁₅N₂O₄ ⁺ [M+H]⁺: 370.1026, found:370.1025; ¹H-NMR (300 MHz, DMSO-d₆) d (ppm): d3.91(3H, s, —OCH₃),d6.90(1H, d, J=8.4 Hz, Ar′—H₅), d7.81-7.88(3H, m, Ar—H_(7,10), Ar′—H₂),d7.92-7.96(3H, m, Ar—H_(4,5), Ar′—H₆), d7.99(1H, s, —NH), d8.11(2H, td,J=Hz, Ar—H_(8,9)), d9.78(1H, br, —OH); and ¹³C-NMR (75 MHz, DMSO-d₆) d(ppm): 56.57, 112.72, 116.37, 119.21, 119.65, 122.05, 122.95, 123.88,126.81, 127.41, 128.42, 133.50, 133.64, 134.87, 135.09, 148.48, 150.87,158.33, 182.85(CO), 183.79(CO).

Embodiment 15 (2-p-Tolyl-1H-anthra[1,2-d]imidazole-6,11-dione, No. 15)

All steps for manufacturing the twany compound No. 15 are identical withthe steps of Embodiment 14, except that vanillin is substituted byp-tolualdehyde (0.7 ml, 5 mmol).

The compound No. 15 has the following characterstics: MW 338.1055(C₂₂H₁₄N₂O₄); R_(f): 0.65 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 3397(NH), 1659(CO); EI-MS m/z: 338(M⁺, 100%), 339(24%) HRMS(ESI-TOF) m/z: calcd for C₂₂H₁₅N₂O₄ ⁺ [M+H]⁺: 339.1128, found: 339.1128;¹H-NMR (300 MHz, CDCl₃) d (ppm): d2.46(3H, s, Ar′—CH₃), d7.37(2H, d,J=8.1 Hz, Ar′—H_(3,5)), d7.79(2H, t, J=3.6 Hz, Ar—H_(7,10)), d8.03(2H,d, J=7.8 Hz, Ar′—H_(2,6)), d8.08(1H, d, J=8.4 Hz, Ar—H₅), d8.21(1H, d,J=8.4 Hz, Ar—H₄), d8.24-8.34(2H, m, Ar—H_(8,9)), d11.21(1H, s, —NH); and¹³C-NMR (75 MHz, CDCl₃) d (ppm): 21.58, 117.89, 121.96, 125.44, 125.75,126.46, 127.00, 127.58, 128.43, 130.00, 133.20, 133.26, 133.72, 133.99,134.38, 142.05, 149.50, 156.86, 182.60(CO), 185.16(CO).

Embodiment 16 (2-(4-Bromophenyl)-1H-anthra[1,2-d]imidazole-6,11-dione,No. 16)

All steps for manufacturing the red brown compound No. 16 are identicalwith the steps of Embodiment 14, except that vanillin is substituted by4-bromobenzaldehyde (0.93 g, 5 mmol).

The compound No. 16 has the following characterstics: MW 402.0004(C₂₁H₁₁N₂O₂Br); R_(f): 0.4 (ethyl acetate: dichloromethane=1:4); IR(KBr) cm⁻¹: 3391(NH), 1658(CO); EI-MS m/z: 402(M⁺, 100%), 404(97%), HRMS(ESI-TOF) m/z: calcd for C₂₁H₁₂N₂O₂Br⁺ [M+H]⁺: 403.0085, found: 403.0073calcd for C₂₁H₁₀N₂O₂Br⁻ [M−H]⁻: 400.9939, found: 400.9923; ¹H-NMR (300MHz, CDCl₃) d (ppm): d7.72(2H, d, J=8.7 Hz, Ar′—H_(3,5)), d7.80-7.83(2H,m, Ar—H_(7,10)), d8.06(2H, d, J=8.7 Hz, Ar′—H_(2,6)), d8.13(1H, d, J=8.4Hz, Ar—H₄), d8.25(1H, d, J=8.4 Hz, Ar—H₅), d8.27-8.36(2H, m,Ar—H_(8,9)), d11.29(1H, s, —NH); and ¹³C-NMR (75 MHz, CDCl₃) d (ppm):122.18, 125.86, 126.11, 126.57, 127.64, 127.69, 128.50, 128.89, 132.61,133.20, 133.35, 133.87, 134.01, 134.57, 149.40, 155.62, 182.63(CO),185.25(CO).

Embodiment 17 (2-(4-Cyanophenyl)-1H-anthra[1,2-d]imidazole-6,11-dione,No. 17)

All steps for manufacturing the yellowish brown compound No. 17 areidentical with the steps of Embodiment 14, except that vanillin issubstituted by 4-cyanobenzaldehyde (0.67 g, 5 mmol).

The compound No. 17 has the following characterstics: MW 349.0851(C₂₂H₁₁N₃O₂); R_(f): 0.65 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 3341(NH), 2229(CN), 1667(CO); HRMS (ESI-TOF) m/z: calcd forC₂₂H₁₂N₃O₂ ⁺ [M+H]⁺: 350.0924, found: 350.0925; ¹H-NMR (300 MHz,CDCl₃)d(ppm): d7.80-7.85(2H, m, Ar—H_(7,10)), d8.06(2H, d, J=8.1 Hz,Ar—H_(3′,5′)), d8.18(1H, d, J=8.4 Hz, Ar—H₅), d8.27-8.32(4H, m,Ar—H_(4,8,2′,6′)), d8.35-8.38(1H), m, Ar—H₉), d11.46(1H, s, —NH); and¹³C-NMR (75 MHz, DMSO-d₆) d (ppm): 114.71, 118.04, 118.52, 122.39,126.39, 126.63, 127.57, 127.75, 129.45, 132.76, 133.04, 133.11, 133.34,133.93, 133.99, 134.70, 149.17, 154.25, 182.56(CO), 185.21(CO).

Embodiment 18(2-(2,5-Dimethoxyphenyl)-1H-anthra[1,2-d]imidazole-6,11-dione, No. 18)

All steps for manufacturing the red brown compound No. 18 are identicalwith the steps of Embodiment 14, except that vanillin is substituted by2,5-dimethoxybenzaldehyde (0.89 g, 5 mmol).

The compound No. 18 has the following characterstics: MW 384.1110(C₂₃H₁₆N₂O₄); R_(f): 0.4 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 3417(NH), 1660(C═O), 1226(C—O); HRMS (ESI-TOF) m/z: calcd forC₂₃H₁₇N₂O₄ ⁺ [M+H]⁺: 385.1183, found: 385.1181; ¹H-NMR (300 MHz, CDCl₃)d (ppm): d3.93(3H, s, Ar5′-OCH₃), d4.21(H, s, Ar_(2′)—OCH₃), d7.09(2H,d, J=1.2 Hz, Ar—H_(3′,4′)), d7.79-7.82(2H, m, Ar—H_(7,10)), d8.13(1H, d,J=8.1 Hz, Ar—H₅ ), d8.13(1H, s, Ar—H_(6′)), d8.25(1H, d, J=8.1 Hz,Ar—H₄), d8.29-8.36(2H, m, Ar—H_(8,9)), d12.37(1H, s, —NH); and ¹³C-NMR(75 MHz, CDCl₃) d (ppm): 56.08, 56.69, 113.13, 113.36, 116.86, 118.14,119.98, 121.92, 124.92, 126.46, 127.54, 129.92, 132.57, 133.43, 133.70,134.06, 134.24, 135.39, 152.20, 154.23, 155.18, 182.82(CO), 184.88(CO).

Embodiment 19(2-(Benzo[d][1,3]dioxol-5-yl)-1H-anthra[1,2-d]imidazole-6,11-dione, No.19)

All steps for manufacturing the red brown compound No. 19 are identicalwith the steps of Embodiment 14, except that vanillin is substituted bypiperonal (0.77 g, 5 mmol).

The compound No. 19 has the following characterstics: MW 368.0797(C₂₂H₁₂N₂O₄); R_(f): 0.45 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 3444(NH), 1670(C═O), 1257(C—O), 1210(C—O); HRMS (ESI-TOF) m/z:calcd for C₂₂H₁₃N₂O₄ ⁺ [M+H]⁺: 369.0867, found: 369.0887; ¹H-NMR (300MHz, CDCl₃) d (ppm): d6.11(2H, s, —OCH₂O—), d7.00(1H, d, J=7.8 Hz,Ar—H_(5′)), d7.67(1H, s, Ar—H_(2′)), d7.79-7.82(2H, m, Ar—H_(7,10)),d8.13(1H, d, J=8.1 Hz, Ar—H₅), d8.24(1H, d, J=7.8 Hz, Ar—H_(6′)),d8.25(1H, d, J=8.1 Hz, Ar—H₄), d8.29-8.36(2H, m, Ar—H_(8,9)), d11.18(1H,s, —NH); and ¹³C-NMR (75 MHz, CDCl₃) d (ppm): 101.93, 107.37, 108.96,117.86, 121.83, 122.05, 122.78, 125.35, 126.52, 127.62, 128.40, 133.27,133.43, 133.76, 134.08, 134.44, 148.71, 149.62, 150.56, 156.55,182.66(CO), 185.27(CO).

Embodiment 20 (Anthra[2,1-c][1,2,5]thiadiazole-6,11-dione, No. 22)

1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in THF (30 mL),and triethylamine (3 mL) is further added thereinto for catalyzationafter thionyl chloride (0.15 g, 20 mmol) is dripped thereinto. Aftermixing and reacting in room temperature for one hour, the reactedmixture is transferred into 200 mL of icy water. After filtering, theprecipitate is collected and recrystallized by hot alcolhol, so as toobtain yellow compound No. 22 with melting point of 227-228° C., and theproduction rate is 74%.

The compound No. 22 has the following characterstics: MW 266.0150(C₁₄H₆N₂O₂S); R_(f): 0.8 (ethyl acetate: dichloromethane=1:4); IR (KBr)cm⁻¹: 1671(CO); EI-MS m/z: 210(57%), 238(64%), 266(M⁺, 100%), HRMS(ESI-TOF) m/z: calcd for C₁₄H₇N₂O₂S⁺ [M+H]⁺: 267.0223, found: 267.0226;¹H-NMR (300 MHz, CDCl₃) d (ppm): d7.84(1H, dd, J=12.15,6.9 Hz, Ar—H₇),d7.85(1H, dd,J=13.2,7.5 Hz, Ar—H₁₀), d8.33(1H, dd, J=22.5, 7.2 Hz,Ar—H₈), d8.33(1H, dd, J=22.5, 7.2 Hz, Ar—H₉), d8.41(1H, d, J=9.3 Hz,Ar—H₅), d8.56(1H, d, J=9.3 Hz, Ar—H₄); and ¹³C-NMR (75 MHz, CDCl₃) d(ppm): 125.07, 126.35, 126.99, 127.34, 127.61, 132.08, 133.47, 134.15,134.75, 135.16, 150.93, 157.99, 181.97(CO), 183.31(CO).

Embodiment 21(2,2-Dimethyl-2,3-dihydro-1H-anthra[1,2-d]imidazole-6,11-dione, No. 20)

1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in dry acetone(100 mL), and concentrated sulfuric acid (0.1 mL) is further addedthereinto. After mixing and reacting in room temperature for 48 hours,the reacted mixture is transferred into a potassium carbonate column.The product is collected and recrystallized by methanol, so as to obtainthe purple compound 20, and the production rate is 31%. In thepurification steps of the Embodiment 21, regular extraction method willreduce the production rate, and thus the basic column is used to removethe acid in the rough extract, so as to increase the production rate.

The compound No. 20 has the following characterstics: Melting point:235-237° C., MW 278.1055 (C₁₇H₁₄N₂O₂); R_(f): 0.5 (ethyl acetate:dichloromethane=1:4); IR (KBr) cm⁻¹: 3419(NH), 3239(NH), 1639 (CO);EI-MS m/z: 263(100%), 278(M⁺, 8.6%), HRMS (ESI-TOF) m/z: calcd forC₁₇H₁₅N₂O₂ ⁺ [M+H]⁺: 279.1128, found: 279.1133; ¹H-NMR (300 MHz,DMSO-d₆) d (ppm): d1.48(6H, s, —CH₃), d6.26(1H, d, J=7.8 Hz, Ar—H₄),d7.37(1H, d, J=7.8 Hz, Ar—H₅), d7.73-7.76(m, 2H, Ar—H_(7,10)), d8.05(s,1H, —NHC—), d8.08-8.12(m, 2H, Ar—H_(8,9)), d8.79(s, 1H, —CNH—); and¹³C-NMR (75 MHz, DMSO-d₆) d (ppm): 30.18, 81.70, 104.02, 108.04, 120.99,123.54, 126.32, 127.07, 133.41, 133.54, 134.79, 135.46, 143.05, 148.12,179.89(CO), 182.47(CO).

Embodiment 22(2-Methyl-2-phenyl-2,3-dihydro-1H-anthra[1,2-d]imidazole-6,11-dione, No.21)

1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved inN,N-dimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL)is further added thereinto after acetophenone (0.5 ml, 6 mmol) is addedthereinto. After mixing and reacting in room temperature for 72 hours,the reacted mixture is transferred into icy water (200 mL) forprecipitation. The precipitate is collected and recrystallized by hotalcohol, so as to obtain the black compound 21, and the production rateis 28%.

The compound No. 21 has the following characterstics: Melting point:368-371° C., MW 340.1212 (C₂₂H₁₆N₂O₂); R_(f): 0.8 (ethyl acetate:dichloromethane=1:4); IR (KBr) cm⁻¹: 3348(NH), 1671 (CO); HRMS (ESI-TOF)m/z: calcd for C₂₂H₁₇N₂O₂ ⁺ [M+H]⁺: 341.1284, found: 341.1033; ¹H-NMR(300 MHz, DMSO-d₆) d (ppm): d1.22(3H, s, —CH₃), d7.56-7.62(3H, m,Ar′—H_(2,4,6)), d7.90-7.94(2H, m, Ar—H_(7,10)), d8.08(1H, d, J=8.1 Hz,Ar—H₅), d8.22(1H, d, J=8.1 Hz, Ar—H₄), d8.18-8.22(2H, m, Ar′—H_(3,5)),d8.40-8.42(2H, m, Ar—H_(8,9)); and ¹³C-NMR (75 MHz, DMSO) d (ppm):28.79, 83.56, 103.62, 109.74, 119.13, 121.35, 124.03, 126.20, 1267.76,128.32, 128.77, 131.31, 132.99, 134.30, 134.45, 143.05, 157.25,182.60(CO), 182.89(CO).

Embodiment 23 (2,3-dimethylnaphtho[2,3-f]quinoxaline-7,12-dione, No. 24)

1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved inN,N-dimethylformamide (30 mL), and concentrated sulfuric acid (0.1 mL)is further added thereinto after methyl vinyl ketone (0.36 g, 5 mmol) isadded thereinto. After mixing and reacting in room temperature for 72hours, the reacted mixture is transferred into icy water (200 mL) forprecipitation. The precipitate is collected and recrystallized by hotalcohol, so as to obtain the black compound 24, and the production rateis 25%.

The compound No. 24 has the following characterstics: Meltingpoint >400° C., MW 288.0899 (C₁₈H₁₂N₂O₂); R_(f): 0.6 (ethyl acetate:dichloromethane=1:4); IR (KBr) cm⁻¹: 1671 (CO); HRMS (ESI-TOF) m/z:calcd for C₁₈H₁₃N₂O₂ ⁺ [M+H]⁺: 289.0988, found: 289.0970; ¹H-NMR (300MHz, DMSO-d₆) d (ppm): d2.72(3H, s, —CH₃), d2.88(3H, s, —CH₃),d7.91-7.94(2H, m, Ar—H_(8,11)), d8.07(1H, d, J=8.4 Hz, Ar—H₅), d8.16(1H,d, J=8.4 Hz, Ar—H₄), d8.19-8.21(2H, m, Ar—H_(9,10)); and ¹³C-NMR (75MHz, DMSO-d₆) d (ppm): 14.91, 30.74, 120.19, 125.46, 126.21, 126.26,127.16, 128.18, 128.87, 133.01, 133.10, 134.19, 134.27, 134.42, 158.87,162.28, 182.49(CO), 183.37(CO).

Embodiment 24 (Naphtho[2,3-f]quinoxaline-7,12-dione, No. 25)

1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved inN,N-dimethylformamide (30 mL), and 40% glyoxal (0.8 g, 5 mml) in EtOH(50 mL) is added thereinto. After reverse flow for 16 hours, the wateris evaperated out, and the reacted mixture is transferred into icy water(200 mL) for precipitation. The precipitate is collected and washed byhot alcohol and dichloromethane repeatedly, so as to obtain the blackcompound 25, and the production rate is 23%.

The compound No. 25 has the following characterstics: Melting point:270-272° C., MW 260.0586 (C₁₆H₈N₂O₂); R_(f): 0.45 (ethyl acetate:dichloromethane=1:4); IR (KBr) cm⁻¹: 3413(NH), 3365(NH), 1626 (CO);EI-MS m/z: 150(54%), 238(73%), 260(M⁺, 100%); HRMS (ESI-TOF) m/z: calcdfor C₁₆H₉N₂O₂ ⁺ [M+H]⁺: 261.0659, found: 261.0663; ¹H-NMR (300 MHz,CDCl₃) d (ppm): d7.82-7.87 (2H, m, Ar—H_(8,11)), d8.29-8.36 (2H, m,Ar—H_(9,10)), d8.48 (1H, d, J=8.7 Hz, Ar—H₅), d8.72 (1H, d, J=8.7 Hz,Ar—H₆), d8.99 (1H, d, J=1.5 Hz, —N═CH—), d9.25 (1H, d, J=1.5 Hz,—CH═N—); and ¹³C-NMR (75 MHz, CDCl₃) d (ppm): 126.72, 127.05, 127.46,130.05, 131.98, 133.77, 134.76, 135.18, 135.88, 135.93, 136.03, 145.42,146.40, 147.77, 183.21(CO), 183.61(CO).

Embodiment 25 (Naphtho[2,3-f]quinoxaline-2,3,7,12(1H,4H)-tetraone, No.26)

1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved inN,N-dimethylformamide (30 mL), and oxalic acid (0.46 g, 5 mmol) andconcentrated sulfuric acid (0.1 mL) is added thereinto. After reverseflow for 16 hours, the reacted mixture is transferred into icy water(200 mL) for precipitation. The precipitate is collected and washed byhot alcohol and, so as to obtain the black compound 26, and theproduction rate is 30%.

The compound No. 25 has the following characterstics: Melting point:245-246° C., MW 292.0484 (C₁₆H₈N₂O₄); R_(f): 0.25 (ethyl acetate:dichloromethane=1:4); IR (KBr) cm⁻¹: 1710 (CO), 1671 (CONH) ; EI-MS m/z:248(100%), 292(M⁺) HRMS (ESI-TOF) m/z: calcd for C₁₆H₉N₂O₄ ⁺ [M+H]⁺:293.0557, found: 293.0568; ¹H-NMR (300 MHz, DMSO-d₆) d (ppm): d7.71 (1H,d, J=8.0 Hz, Ar—H₅), d7.93-7.98 (2H, m, Ar—H_(8,11)), d8.04 (1H, d,J=8.0 Hz, Ar—H₆), d8.17-8.24 (2H, m, Ar—H_(9,10)), d8.99 (1H, d, J=1.5Hz, —NH—), d9.25 (1H, d, J=1.5 Hz, —NH—); and ¹³C-NMR (75 MHz, DMSO-d6)d (ppm); 118.08, 120.52, 122.87, 126.26, 126.34, 126.78, 127.71, 128.17,129.58, 134.48, 134.55, 135.07, 154.64(NHCO), 154.73(NHCO), 180.08(CO),181.07(CO).

The chemical formula, production rates and melting points of theabove-mentioned heteroannelated anthraquinone derivatives of series Aare illustrated in Table 1, and the chemical formula, production ratesand melting points of the above-mentioned heteroannelated anthraquinonederivatives of serieses B, C and D are described in the embodiments,respectively.

TABLE 1

Melting point Production Compound No. R₁ (° C.) Rate (%) 2 —CH₃ >400 673 —CH₂Cl 272-273 86 4 —CH₂CH₃ 193-194 39 5 —CH(CH₃)₂ 199-200 41 6—(CH₂)₃CH₃ 192-193 36 7 —CH(CH₃)CH₂CH₃ 118-119 40 8 —CH(CH₃)₃ 209-210 379 —(CH₂)₆CH₃ 85-87 38 10 —CH═CHCH₂CH₃ 117-119 33 11 —C₆H₅ 232-233 74 12—C₆H₄-p-N(CH₃)₂ 239-241 79 13 —C₆H₄-p-NO₂ 342-343 89 14—C₆H₃-p-OH-m-OCH₃ 230-231 47 15 —C₆H₄-p-CH₃ 256-257 76 16 —C₆H₄-p-Br302-303 75 17 —C₆H₄-p-CN 353-354 77 18 —C₆H₃-o,m-(OCH₃)₂ 251-252 74 193,4-benzdioxole 300-301 81

Telomeric repeat amplification protocol (TRAP) is employed to detect theeffect of the heteroannelated anthraquinone derivatives synthesized inthe present invention for inhibinting the telomerase activity. In thefirst stage of this method, the telemerase is used to prolong theoligonucleotide with telomere sequence in the conditions of 90° C. for10 minutes, 72° C. for 3 minutes, 50° C. for 60 seconds and 94° C. for30 seconds (TSG4 primer: 5′-GGG ATT GGG ATT GGG ATT GGG TT-3′) In thesecond stage, different compounds are added into the telomerase reactedproduct to further replicate the telomere product by PCR (CX primer:5′-CCCTTA CCCTTA CCCTTA CCCTAA-3′). When the compound inhibits thetelomerase activity, the replication reaction can not be resumed. ThePCR conditions includes 39 cycles of PCR reaction in 50° C. for 30seconds, 72° C. for 60 seconds for 39 PCR cycles, followed by one cycleof reaction in 94° C. for 30 seconds, 50° C. for 30 seconds, 72° C. for30 seconds and 72° C. for 1 minute, and the reaction is ended in 4° C.The PCR product is analyzed by electrophoresis using 10% acrylamide gel.In the electrophoresis results, the positive control (P) is sterilewater (dddH₂O), and the negative control (N) is 5 μl 0.1 mg/mL RNase A(CLONTECH). The positive control (P) produces lots of telomere fragment,while the negative control (N) does not. The compounds provided by thepresent invention inhibit the telomerase activity by stabilizingG-quadruplex structures and blocking the interaction between telomeraseand telomere, or directly inhibit the telomerase activity, so as toinhibit the prologation of telomere. It is found in the presentexperiments that the Embodiments A4 and A5 have better inhibitioneffects.

In addition, it is found in the in vitro experiments performed by thedevelopment therapeutics program of US cancer research center that theheteroannelated anthraquinone derivatives synthesized in the presentinvention have various inhibition effects on different cancer cell linesat 1.0×10⁻⁵ molal concentration (M) as shown in Table 2. For example,the Embodiment A2 of the present invention inhibits the growth of breastcancer cell HS578T, and the Embodiment B1 has overall and the mostobvious inhibition on different cancer cells. Therefore, theheteroannelated anthraquinone derivatives synthesized in the presentinvention are potential drugs for inhibiting cancer cells.

TABLE 2 No. 22 No. 4 No. 20 No. 25 No. 26 Non-small cell lung cancercell HOP-62 −100.00 97.73 XXX XXX XXX HOP-92 XXX 41.43 5.10 XXX −15.08Colorectal cancer cell HCC-2998 −50.00 67.67 136.96 −7.15 77.59 Breastcancer cell HS 578T −7.40 −18.58 XXX XXX XXX MCF7 −50.74 69.82 83.5839.68 85.17 MDA-MB-435 −87.88 84.39 124.56 102.03 144.42 MDA-MB-468−73.17 XXX 77.25 75.28 38.35 T-47D −45.52 63.05 82.96 85.19 87.10 Ovarycancer cell IGROV1 −88.34 XXX −2.80 3.44 13.36 OVCAR-4 −94.43 48.8180.14 94.22 103.31 Blood cancer cell MOLT-4 −40.09 64.17 116.41 22.91121.52 Kidney cancer cell ACHN −94.31 24.97 50.17 46.52 81.33 SN12C−73.27 68.53 91.98 64.65 94.07 UO-31 −79.30 23.94 30.65 51.45 61.43 Skincancer cell LOX IMV1 −50.6 39.98 61.88 44.18 96.94 MALME-3M −71.54 56.94155.47 180.88 149.83 SK-MEL-2 −73.16 40.07 8.04 6.66 21.96 UACC-257−83.07 39.69 118.22 91.06 118.21 UACC-62 −82.32 51.35 67.58 90.47 95.25CNS cancer cell SF-539 −47.11 83.16 93.56 40.72 101.16 U251 −89.26 60.1387.84 63.47 95.92 Mean 2.68 58.42 80.41 69.36 100.83 Delta 102.68 77.0083.21 76.51 115.91 Range 230.09 120.88 158.27 188.03 289.23 XXX: notdetected

The detailed in-vitro testing results of dose response of the CompoundNo. 22 obtained from National Cancer Institute DevelopmentalTherapeutics Program are shown in Tables 3-1 to 3-9.

The detailed in-vitro testing results of dose response of the CompoundNo. 4 obtained from National Cancer Institute Developmental TherapeuticsProgram are shown in Tables 4-1 to 4-9.

The detailed in-vitro testing results of dose response of the CompoundNo. 25 obtained from National Cancer Institute DevelopmentalTherapeutics Program are shown in Tables 5-1 to 5-9.

TABLE 3-1 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.445 1.624 1.589 1.503 1.323 0.4720.470 97 90 74 2 2 2.18E−6 >1.00E−4 >1.00E−4 HL-60 (TB) 0.744 2.1752.214 2.209 2.079 0.461 0.421 103 102 93 −38 −43 2.14E−65.13E−6 >1.00E−4 K-562 0.180 1.220 1.232 1.174 1.038 0.375 0.165 101 9683 19 −8 3.23E−6 4.92E−5 >1.00E−4 MOLT-4 0.455 1.447 1.444 1.462 1.1990.274 0.280 97 99 73 −40 −38 1.59E−6 4.43E−6 >1.00E−4 RPMI-8226 0.6541.899 1.899 1.820 1.418 0.653 0.523 100 94 61 — −20 1.53E−69.91E−6 >1.00E−4 SR 0.167 0.676 0.718 0.738 0.669 0.374 0.278 108 112 9941 −22 6.89E−6 >1.00E−4 >1.00E−4

TABLE 3-2 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Non-Small Cell Lung Cancer A549/ATCC 0.110 0.5500.566 0.518 0.513 0.081 0.091 104 93 92 −27 −18 2.25E−6 5.94E−6 >1.00E−4EKVX 0.652 1.960 1.914 1.813 1.745 0.554 0.251 96 89 84 −15 −62 2.19E−67.03E−6 5.65E−5 HOP-62 0.342 1.187 1.242 1.242 1.243 0.380 0.175 107 107107 4 −49 3.59E−6 1.21E−5 >1.00E−4 HOP-92 0.770 1.201 1.179 1.150 1.1740.765 0.560 95 88 94 −1 −27 2.91E−6 9.84E−6 >1.00E−4 NCI-H226 1.0031.740 1.718 1.701 1.556 1.467 0.956 97 95 75 63 −5 1.56E−58.53E−5 >1.00E−4 NCI-H23 0.418 1.199 1.209 1.125 0.775 0.265 0.271 10191 46 −37 −35 8.02E−7 3.59E−6 >1.00E−4 NCI-H322M 0.347 0.840 0.856 0.9220.940 0.890 0.555 103 116 120 110 42 7.64E−5 >1.00E−4 >1.00E−4 NCI-H4600.245 1.818 1.818 1.767 1.614 0.116 0.104 100 97 87 −53 −58 1.84E−64.19E−6 9.54E−6 NCI-H522 0.541 2.032 2.079 2.073 1.887 0.634 0.441 103103 90 6 −18 3.01E−6 1.78E−5 >1.00E−4

TABLE 3-3 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Colon Cancer COLO 205 0.199 0.969 0.927 0.872 0.9570.069 0.057 95 87 98 −66 −71 1.97E−6 3.98E−6 8.04E−6 HCC-2998 0.2680.572 0.599 0.581 0.588 0.098 0.081 109 103 105 −63 −70 2.12E−6 4.20E−68.32E−6 HCT-116 0.138 0.938 0.927 0.912 0.863 0.145 0.095 99 97 91 1 −312.84E−6 1.06E−5 >1.00E−4 HCT-15 0.285 1.440 1.554 1.485 1.323 0.2540.138 110 104 90 −11 −52 2.49E−6 7.80E−6 9.06E−5 HT29 0.231 1.387 1.4321.444 1.403 0.195 0.108 104 105 101 −16 −53 2.75E−6 7.36E−6 8.10E−5 KM120.217 0.841 0.884 0.889 0.861 0.567 0.103 107 108 103 56 −53 1.14E−53.28E−5 9.48E−5 SW-620 0.175 1.174 1.231 1.201 1.240 0.633 0.056 106 103107 46 −68 8.55E−6 2.52E−5 6.92E−5

TABLE 3-4 Log10 Concentration Panel/ Time Mean Optical Densities PercentGrowth Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 CNS Cancer SF-268 0.357 0.951 0.959 0.938 0.893 0.4590.193 101 98 90 17 −46 3.55E−6 1.87E−5 >1.00E−4 SF-295 0.415 1.524 1.5501.579 1.527 0.404 0.202 102 105 100 −3 −51 3.08E−6 9.40E−6 9.39E−5SF-539 0.574 1.690 1.578 1.517 1.499 0.006 0.012 90 84 83 −99 −981.52E−6 2.86E−6 5.38E−6 SNB-19 0.464 1.328 1.349 1.339 1.330 0.067 0.008102 101 100 −86 −98 1.86E−6 3.46E−6 6.43E−6 SNB-75 0.640 1.050 0.9500.911 0.957 −0.004 −0.009 76 66 77 −100 −100 1.42E−6 2.73E−6 5.22E−6U251 0.220 1.137 1.194 1.177 0.939 0.086 0.082 106 104 78 −61 −631.60E−6 3.65E−6 8.32E−6

TABLE 3-5 Log10 Concentration Panel/ Time Mean Optical Densities PercentGrowth Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Melanoma LOX 0.363 2.033 2.046 2.006 1.219 0.2120.244 101 98 51 −42 −33 1.03E−6 3.56E−6 >1.00E−4 IMVI MALME- 0.229 0.4810.487 0.520 0.512 0.107 0.065 102 115 112 −53 −72 2.37E−6 4.76E−69.55E−6 3M M14 0.339 1.395 1.398 1.394 1.411 0.232 0.199 100 100 102 −32−41 2.44E−6 5.78E−6 >1.00E−4 SK- 0.284 0.761 0.810 0.806 0.731 0.2210.194 110 109 94 −22 −32 2.38E−6 6.42E−6 >1.00E−4 MEL-2 SK-MEL- 0.3001.110 1.135 1.161 1.165 0.703 0.023 103 106 107 50 −93 9.88E−6 2.24E−55.03E−5 28 SK- 0.540 2.145 2.107 1.896 1.477 −0.009 −0.002 98 85 58 −100−100 1.13E−6 2.34E−6 4.83E−6 MEL-5 UACC- 0.493 0.980 0.962 0.986 0.8700.083 0.047 96 101 77 −83 −91 1.48E−6 3.03E−6 6.21E−6 257 UACC-62 0.4311.918 1.751 1.787 1.798 0.331 0.214 89 91 92 −23 −50 2.31E−6 6.29E−69.62E−6

TABLE 3-6 Log10 Concentration Panel/ Time Mean Optical Densities PercentGrowth Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Ovarian Cancer OVCAR-3 0.305 0.775 0.852 0.821 0.7100.216 0.075 116 110 86 −29 −75 2.06E−6 5.59E−6 2.82E−5 OVCAR-4 0.3630.880 0.916 0.850 0.531 −0.015 −0.014 107 94 32 −100 −100 5.20E−71.76E−6 4.19E−6 OVCAR-5 0.446 0.930 0.924 0.903 0.953 0.192 0.187 99 94105 −57 −58 2.18E−6 4.44E−6 9.06E−6 OVCAR-8 0.299 1.154 1.200 1.1710.695 0.169 0.185 105 102 46 −43 −38 8.59E−7 3.28E−6 >1.00E−4 SK-OV-30.530 1.224 1.239 1.154 1.150 0.414 0.015 102 90 89 −22 −97 2.26E−66.35E−6 2.36E−5

TABLE 3-7 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Renal Cancer 786-0 0.450 1.828 1.894 1.916 2.0490.517 0.130 105 106 116 5 −71 3.93E−6 1.16E−5 5.27E−5 A498 0.605 1.4811.527 1.518 1.449 1.479 1.340 105 104 96 10084 >1.00E−4 >1.00E−4 >1.00E−4 ACHN 0.355 1.317 1.389 1.452 1.220 0.0630.218 107 114 90 −82 −39 1.71E−6 3.33E−6 — CAKI-1 0.294 0.870 0.8130.844 0.798 0.226 0.099 90 95 88 −23 −66 2.18E−6 6.16E−6 4.15E−5 SN12C0.304 1.076 1.007 1.097 0.948 0.284 0.199 91 103 83 −7 −35 2.35E−68.42E−6 >1.00E−4 TK-10 0.362 0.792 0.865 0.935 0.983 0.868 0.337 117 133144 118 −7 3.49E−5 8.80E−5 >1.00E−4 UO-31 0.147 0.498 0.539 0.562 0.4990.041 0.050 111 118 100 −72 −66 1.95E−6 3.81E−6 7.41E−6

TABLE 3-8 Log10 Concentration Panel/ Time Mean Optical Densities PercentGrowth Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Prostate Cancer PC-3 0.372 1.158 1.128 1.096 1.0500.459 0.402 96 92 86 11 4 3.03E−6 >1.00E−4 >1.00E−4 DU-145 0.230 0.7040.750 0.772 0.752 0.425 −0.002 110 114 110 41 −100 7.41E−6 1.95E−54.42E−5

TABLE 3-9 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Breast Cancer MCF7 0.282 1.325 1.202 1.081 0.9290.101 0.104 88 77 62 −64 −63 1.24E−6 3.10E−6 7.72E−6 NCI/ADR-RES 0.4361.282 1.343 1.296 0.608 0.395 0.363 107 102 20 −10 −17 4.32E−74.80E−6 >1.00E−4 MDA-MB-231/ 0.478 1.197 1.226 1.100 1.063 0.510 0.525104 87 81 4 6 2.56E−6 >1.00E−4 >1.00E−4 ATCC HS 578T 0.413 1.287 1.3621.410 1.289 0.663 0.595 109 114 100 29 21 5.03E−6 >1.00E−4 >1.00E−4MDA-MB-435 0.280 1.351 1.350 1.373 1.160 0.190 0.137 100 102 82 −32 −511.91E−6 5.23E−6 8.78E−5 BT-549 0.254 0.524 0.503 0.529 0.594 0.426 0.12292 102 126 64 −52 1.31E−5 3.55E−5 9.62E−5 T-47D 0.377 0.816 0.775 0.7630.473 0.156 0.150 91 88 22 −59 −60 3.75E−7 1.87E−6 7.79E−6 MDA-MB-4682.275 3.124 3.096 3.134 3.152 0.022 0.031 97 101 103 −99 −99 1.83E−63.24E−6 5.72E−6

TABLE 4-1 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.321 1.468 1.505 1.400 1.407 0.9100.488 103 94 95 51 15 1.09E−5 >1.00E−4 >1.00E−4 HL-60(TB) 0.691 1.6281.626 1.630 1.639 1.092 0.873 100 100 101 43 197.53E−6 >1.00E−4 >1.00E−4 K-562 0.269 1.578 1.498 1.469 1.412 1.0970.903 94 92 87 63 48 7.83E−5 >1.00E−4 >1.00E−4 MOLT-4 0.734 2.108 2.0762.057 2.015 1.402 0.726 98 96 93 49 −1 9.31E−6 9.51E−5 >1.00E−4RPMI-8226 0.443 1.284 1.259 1.121 1.060 0.547 0.390 97 81 73 12 −122.42E−6 3.21E−5 >1.00E−4

TABLE 4-2 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Non-Small Cell Lung Cancer A549/ATCC 0.193 0.8950.832 0.892 0.876 0.614 0.315 91 100 97 60 17 1.71E−5 >1.00E−4 >1.00E−4EKVX 0.897 1.986 1.856 1.792 1.540 1.059 0.894 88 82 59 15 — 1.60E−69.43E−5 >1.00E−4 HOP-62 0.474 1.375 1.283 1.318 1.254 1.127 0.814 90 9487 72 38 4.42E−5 >1.00E−4 >1.00E−4 HOP-92 0.892 1.397 1.360 1.297 1.2141.134 1.010 93 80 64 48 23 7.38E−6 >1.00E−4 >1.00E−4 NCI-H226 0.8171.747 1.612 1.642 1.608 1.404 1.022 85 89 85 63 222.08E−5 >1.00E−4 >1.00E−4 NCI-H23 0.485 1.638 1.547 1.500 1.333 1.0510.732 92 88 74 49 21 9.17E−6 >1.00E−4 >1.00E−4 NCI-H322M 0.721 1.8441.757 1.746 1.643 1.177 0.976 92 91 82 41 23 5.94E−6 >1.00E−4 >1.00E−4NCI-H460 0.233 1.933 1.666 1.630 1.494 0.651 0.266 84 82 74 25 23.07E−6 >1.00E−4 >1.00E−4 NCI-H522 0.713 2.605 2.403 2.370 2.360 1.7351.328 89 88 87 54 32 1.54E−5 >1.00E−4 >1.00E−4

TABLE 4-3 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Colon Cancer COLO 205 0.213 1.012 0.960 0.958 0.8910.544 0.284 93 93 85 41 9 6.36E−6 >1.00E−4 >1.00E−4 HCC-2998 0.660 2.1341.963 2.044 1.983 1.527 0.988 88 94 90 59 22 1.74E−5 >1.00E−4 >1.00E−4HCT-116 0.248 2.129 1.969 2.043 1.716 1.044 0.450 92 95 78 42 116.10E−6 >1.00E−4 >1.00E−4 HCT-15 0.248 1.514 1.391 1.422 1.121 0.5880.348 90 93 69 27 8 2.82E−6 >1.00E−4 >1.00E−4 HT29 0.151 0.999 0.9510.998 0.893 0.557 0.241 94 100 88 48 11 8.84E−6 >1.00E−4 >1.00E−4 KM120.268 1.092 1.072 1.040 1.003 0.625 0.373 98 94 89 43 137.15E−6 >1.00E−4 >1.00E−4 SW-620 0.150 0.998 0.991 0.968 0.902 0.4800.202 99 96 89 39 6 5.97E−6 >1.00E−4 >1.00E−4

TABLE 4-4 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 CNS Cancer SF-268 0.319 1.084 0.986 1.053 0.990 0.7580.530 87 96 88 57 28 1.77E−5 >1.00E−4 >1.00E−4 SF-295 0.695 1.929 1.7851.806 1.549 1.127 0.812 88 90 69 35 9 3.65E−6 >1.00E−4 >1.00E−4 SF-5390.639 1.878 1.642 1.666 1.631 1.204 0.798 81 83 80 46 137.46E−6 >1.00E−4 >1.00E−4 SNB-19 0.656 1.341 1.229 1.299 1.289 1.0730.921 84 94 92 61 39 3.09E−5 >1.00E−4 >1.00E−4 SNB-75 0.661 1.282 1.0681.070 0.965 0.916 0.770 66 66 49 41 17 8.72E−7 >1.00E−4 >1.00E−4 U2510.280 1.443 1.369 1.393 1.260 0.854 0.597 94 96 84 49 279.58E−6 >1.00E−4 >1.00E−4

TABLE 4-5 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Melanoma LOX IMVI 0.316 2.231 2.245 2.058 1.903 0.9560.508 101 91 83 33 10 4.61E−6 >1.00E−4 >1.00E−4 MALME-3M 0.694 1.2471.174 1.161 1.153 0.835 0.683 87 84 83 26 −2 3.75E−6 8.69E−5 >1.00E−4M14 0.435 1.796 1.627 1.731 1.500 1.119 0.776 88 95 78 50 251.02E−5 >1.00E−4 >1.00E−4 SK-MEL-28 0.239 0.861 0.794 0.762 0.730 0.5370.211 89 84 79 48 −12 8.58E−6 6.36E−5 >1.00E−4 SK-MEL-5 0.639 2.0891.284 1.249 1.501 0.607 0.515 44 42 59 −5 −19 . 8.36E−6 >1.00E−4UACC-257 0.437 0.825 0.763 0.761 0.808 0.694 0.506 84 84 96 66 182.16E−5 >1.00E−4 >1.00E−4 UACC-62 0.639 2.092 1.844 1.978 1.874 1.2311.015 83 92 85 41 26 6.18E−6 >1.00E−4 >1.00E−4

TABLE 4-6 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Ovarian Cancer IGROV1 0.518 1.681 1.555 1.537 1.1740.583 0.421 89 88 56 6 −19 1.34E−6 1.69E−5 >1.00E−4 OVCAR-3 0.283 0.7460.745 0.773 0.713 0.549 0.319 100 106 93 57 8 1.41E−5 >1.00E−4 >1.00E−4OVCAR-4 0.565 1.740 1.719 1.694 1.535 0.999 0.745 98 96 83 37 155.18E−6 >1.00E−4 >1.00E−4 OVCAR-5 0.395 0.931 0.865 0.884 0.900 0.8520.637 88 91 94 85 45 7.57E−5 >1.00E−4 >1.00E−4 OVCAR-8 0.228 0.904 0.8810.841 0.847 0.623 0.393 96 91 92 58 24 1.77E−5 >1.00E−4 >1.00E−4 SK-OV-30.566 1.432 1.392 1.359 1.223 0.673 0.687 95 92 76 12 142.55E−6 >1.00E−4 >1.00E−4

TABLE 4-7 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Renal Cancer 786-0 0.664 2.228 2.288 2.259 2.1431.725 1.264 104 102 95 68 38 4.02E−5 >1.00E−4 >1.00E−4 A498 0.564 1.2241.202 1.221 1.065 0.793 0.453 94 97 74 34 −20 3.89E−6 4.27E−5 >1.00E−4ACHN 0.385 1.455 1.393 1.299 1.047 0.537 0.366 94 85 62 14 −5 1.77E−65.46E−5 >1.00E−4 CAKI-1 0.547 1.711 1.680 1.610 1.430 0.780 0.654 97 9176 20 9 2.90E−6 >1.00E−4 >1.00E−4 SN12C 0.617 1.996 1.639 1.719 1.6401.247 0.872 74 80 74 46 18 7.05E−6 >1.00E−4 >1.00E−4 TK-10 0.612 1.2451.212 1.327 1.088 0.856 0.633 95 113 75 39 3 4.88E−6 >1.00E−4 >1.00E−4UO-31 0.517 1.634 1.496 1.444 1.268 0.680 0.518 88 83 67 15 .2.12E−6 >1.00E−4 >1.00E−4

TABLE 4-8 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Prostate Cancer PC-3 0.306 1.233 1.197 1.233 1.1700.807 0.572 96 100 93 54 29 1.44E−5 >1.00E−4 >1.00E−4 DU-145 0.226 0.7240.713 0.713 0.666 0.411 0.344 98 98 88 37 24 5.62E−6 >1.00E−4 >1.00E−4

TABLE 4-9 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Breast Cancer MCF7 0.249 1.082 0.960 0.880 0.6970.556 0.240 85 76 54 37 −4 1.68E−6 8.14E−5 >1.00E−4 NCI/ADR-RES 0.4611.540 1.483 1.524 1.421 1.010 0.530 95 99 89 51 61.05E−5 >1.00E−4 >1.00E−4 MDA-MB-231/ATCC 0.453 1.133 1.121 1.097 1.0630.820 0.700 98 95 90 54 36 1.66E−5 >1.00E−4 >1.00E−4 HS 578T 0.296 0.7040.734 0.736 0.526 0.393 0.202 107 108 56 24 −32 1.56E−6 2.67E−5 >1.00E−4MDA-MB-435 0.515 1.859 1.815 1.744 1.748 1.404 1.019 97 91 92 66 373.65E−5 >1.00E−4 >1.00E−4 BT-549 1.015 2.001 2.009 2.006 1.951 1.6061.166 101 100 95 60 15 1.67E−5 >1.00E−4 >1.00E−4 T-47D 0.415 0.852 0.8760.824 0.755 0.554 0.459 105 94 78 32 10 4.00E−6 >1.00E−4 >1.00E−4MDA-MB-468 0.494 1.038 0.944 0.977 0.923 0.654 0.458 83 89 79 29 −73.83E−6 6.33E−5 >1.00E−4

TABLE 5-1 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Leukemia CCRF-CEM 0.230 0.806 0.751 0.755 0.622 0.3580.344 90 91 68 22 20 2.46E−6 >1.00E−4 >1.00E−4 HL-60(TB) 0.336 0.6400.587 0.540 0.478 0.347 0.153 83 67 47 3 −54 6.77E−7 1.15E−5 8.37E−5K-562 0.086 0.900 0.851 0.422 0.332 0.225 0.166 94 41 30 17 106.83E−8 >1.00E−4 >1.00E−4 MOLT-4 0.273 1.048 0.959 0.900 0.830 0.5290.302 89 81 72 33 4 3.65E−6 >1.00E−4 >1.00E−4 RPMI-8226 0.429 1.3311.245 1.161 0.926 0.702 0.535 90 81 55 30 12 1.61E−6 >1.00E−4 >1.00E−4

TABLE 5-2 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Non-Small Cell Lung Cancer A549/ATCC 0.551 1.8571.771 1.792 1.552 1.022 0.594 93 95 77 36 3 4.53E−6 >1.00E−4 >1.00E−4EKVX 0.439 1.025 1.032 0.960 0.904 0.584 0.421 101 89 79 25 −4 3.45E−67.21E−5 >1.00E−4 HOP-62 0.233 0.934 0.879 0.811 0.799 0.512 0.255 92 8281 40 3 5.64E−6 >1.00E−4 >1.00E−4 HOP-92 0.785 1.360 1.334 1.260 1.2311.206 0.829 95 83 78 73 8 2.25E−5 >1.00E−4 >1.00E−4 NCI-H226 0.780 1.7651.631 1.577 1.497 1.415 0.769 86 81 73 64 −1 1.66E−5 9.52E−5 >1.00E−4NCI-H23 0.452 1.356 1.281 1.242 1.213 0.950 0.407 92 87 84 55 −101.20E−5 7.03E−5 >1.00E−4 NCI-H322M 0.310 0.751 0.736 0.709 0.722 0.5920.307 96 90 93 64 −1 1.63E−5 9.61E−5 >1.00E−4 NCI-H460 0.229 1.901 1.8691.815 1.309 0.507 0.179 98 95 65 17 −22 2.01E−6 2.69E−5 >1.00E−4NCI-H522 0.336 1.040 0.966 0.942 0.906 0.579 0.226 89 86 81 35 −334.64E−6 3.25E−5 >1.00E−4

TABLE 5-3 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Colon Cancer COLO 205 0.211 0.782 0.739 0.704 0.6340.376 0.138 92 86 74 29 −35 3.40E−6 2.84E−5 >1.00E−4 HCC-2998 0.3261.161 1.135 1.113 0.759 0.658 0.315 97 94 52 40 −3 1.40E−68.35E−5 >1.00E−4 HCT-116 0.142 1.101 1.060 1.089 1.018 0.666 0.175 96 9991 55 3 1.23E−5 >1.00E−4 >1.00E−4 HCT-15 0.274 1.667 1.502 1.449 1.3430.784 0.266 88 84 77 37 −3 4.63E−6 8.43E−5 >1.00E−4 HT29 0.174 1.1861.176 1.131 0.925 0.636 0.184 99 95 74 46 1 7.01E−6 >1.00E−4 >1.00E−4KM12 0.224 0.967 0.884 0.896 0.786 0.522 0.185 89 90 76 40 −18 5.26E−64.95E−5 >1.00E−4 SW-620 0.159 1.008 0.960 0.901 0.649 0.369 0.118 94 8758 25 −26 1.71E−6 3.08E−5 >1.00E−4

TABLE 5-4 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 CNS Cancer SF-268 0.347 1.080 1.051 1.020 0.981 0.5980.357 96 92 86 34 1 4.98E−6 >1.00E−4 >1.00E−4 SF-295 0.598 1.530 1.4401.375 1.481 0.828 0.456 90 83 95 25 −24 4.35E−6 3.23E−5 >1.00E−4 SF-5390.657 1.869 1.748 1.719 1.430 0.937 0.601 90 88 64 23 −9 2.18E−65.37E−5 >1.00E−4 SNB-19 0.279 0.934 0.892 0.887 0.867 0.650 0.307 94 9390 57 4 1.34E−5 >1.00E−4 >1.00E−4 SNB-75 0.649 1.457 1.324 1.350 1.2641.079 0.740 83 87 76 53 11 1.19E−5 >1.00E−4 >1.00E−4 U251 0.231 1.2831.242 1.205 1.172 0.604 0.184 96 93 89 35 −21 5.38E−6 4.29E−5 >1.00E−4

TABLE 5-5 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Melanoma LOX IMVI 0.311 2.100 1.927 1.830 1.766 0.8670.244 90 85 81 31 −22 4.20E−6 3.89E−5 >1.00E−4 MALME-3M 0.403 0.7250.715 0.696 0.687 0.498 0.145 97 91 88 30 −64 4.48E−6 2.07E−5 7.08E−5M14 0.352 1.249 1.202 1.164 1.149 0.659 0.356 95 91 89 34 .5.14E−6 >1.00E−4 >1.00E−4 SK-MEL-2 0.212 0.515 0.505 0.471 0.521 0.3880.171 97 85 102 58 −20 1.27E−5 5.59E−5 >1.00E−4 SK-MEL-28 0.363 1.0411.041 1.050 1.070 0.873 0.352 100 101 104 75 −3 2.10E−5 9.11E−5 >1.00E−4SK-MEL-5 0.644 2.455 2.270 2.280 2.136 1.150 0.049 90 90 82 28 −923.93E−6 1.71E−5 4.44E−5 UACC-257 0.466 1.070 1.040 0.996 1.063 0.8150.413 95 88 99 58 −11 1.30E−5 6.83E−5 >1.00E−4 UACC-62 0.828 2.206 2.1031.986 2.030 1.655 0.662 92 84 87 60 −20 1.33E−5 5.61E−5 >1.00E−4

TABLE 5-6 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Ovarian Cancer IGROV1 0.313 1.001 0.932 0.824 0.7350.543 0.229 90 74 61 33 −27 2.55E−6 3.59E−5 >1.00E−4 OVCAR-3 0.237 0.7430.766 0.717 0.626 0.260 0.137 104 95 77 4 −42 2.34E−6 1.25E−5 >1.00E−4OVCAR-4 0.449 1.297 1.311 1.220 1.075 0.883 0.472 102 91 74 51 31.05E−5 >1.00E−4 >1.00E−4 OVCAR-5 0.372 1.072 1.054 0.999 1.056 0.9120.506 97 90 98 77 19 5.93E−5 >1.00E−4 >1.00E−4 OVCAR-8 0.271 1.191 1.1631.091 1.031 0.606 0.390 97 89 83 36 13 5.07E−6 >1.00E−4 >1.00E−4 SK-OV-30.521 1.313 1.243 1.228 1.150 0.874 0.586 91 89 79 44 8 6.95E−6 >1.00E−4>1.00E−4

TABLE 5-7 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Renal Cancer 786-0 0.611 2.118 2.089 2.131 2.1861.320 0.835 98 101 104 47 15 8.87E−6 >1.00E−4 >1.00E−4 A498 0.575 1.1161.079 1.034 1.058 0.839 0.456 93 85 89 49 −21 9.31E−6 5.03E−5 >1.00E−4ACHN 0.370 1.672 1.642 1.508 1.367 0.776 0.397 98 87 77 31 23.85E−6 >1.00E−4 >1.00E−4 CAKI-1 0.369 1.388 1.325 1.271 1.260 0.7620.409 94 89 87 39 4 5.83E−6 >1.00E−4 >1.00E−4 RXF 393 0.826 2.065 2.0241.973 1.829 1.355 0.919 97 93 81 43 7 6.43E−6 >1.00E−4 >1.00E−4 SN12C0.518 1.551 1.421 1.257 1.326 1.108 0.508 87 71 78 57 −2 1.32E−59.27E−5 >1.00E−4 TK-10 0.190 0.513 0.518 0.464 0.457 0.306 0.196 102 8583 36 2 5.00E−6 >1.00E−4 >1.00E−4 UO-31 0.483 1.268 1.113 1.058 1.0590.678 0.475 80 73 73 25 −2 3.02E−6 8.59E−5 >1.00E−4

TABLE 5-8 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Prostate Cancer PC-3 0.138 0.476 0.479 0.449 0.3730.306 0.308 101 92 69 50 50 . >1.00E−4 >1.00E−4 DU-145 0.200 0.762 0.7750.735 0.739 0.515 0.103 102 95 96 56 −49 1.14E−5 3.43E−5 >1.00E−4

TABLE 5-9 Log10 Concentration Time Mean Optical Densities Percent GrowthPanel/Cell Line Zero Ctrl −8.0 −7.0 −6.0 −5.0 −4.0 −8.0 −7.0 −6.0 −5.0−4.0 GI50 TGI LC50 Breast Cancer MCF7 0.451 2.118 1.797 1.793 1.2010.894 0.318 81 80 45 27 −29 7.22E−7 2.98E−5 >1.00E−4 NCI/ADR-RES 0.4761.685 1.621 1.586 1.530 0.934 0.567 95 92 87 38 85.68E−6 >1.00E−4 >1.00E−4 MDA-MB-231/ATCC 0.444 1.084 1.085 1.008 0.9870.854 0.535 100 88 85 64 14 1.91E−5 >1.00E−4 >1.00E−4 HS 578T 0.4150.913 0.854 0.861 0.819 0.710 0.405 88 90 81 59 −2 1.41E−59.14E−5 >1.00E−4 MDA-MB-435 0.426 1.511 1.527 1.479 1.525 1.043 0.021101 97 101 57 −95 1.11E−5 2.37E−5 5.04E−5 BT-549 0.571 1.144 1.114 1.0571.044 0.886 0.562 95 85 83 55 −2 1.22E−5 9.35E−5 >1.00E−4 T-47D 0.3930.891 0.819 0.794 0.747 0.674 0.362 85 80 71 56 −8 1.26E−5 7.51E−5>1.00E−4

While the invention has been described in terms of what is presentlyconsidered to be the most practical and preferred embodiments, it is tobe understood that the invention needs not be limited to the disclosedembodiments. On the contrary, it is intended to cover variousmodifications and similar arrangements included within the spirit andscope of the appended claims which are to be accorded with the broadestinterpretation so as to encompass all such modifications and similarstructures.

Citations:

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1. A heteroannelated anthraquinone derivative compound represented by aformula (I):

wherein R₁ is a substituent being one selected from a group consistingof: i) a first substituent being one selected from a group consisting ofa hydryl group, an amino group, a nitro group, a hydroxyl group and acyan group; ii) a second substituent being one selected from a groupconsisting of (CH₂)_(n)X, a straight (CH₂)_(n) alkyl group, a (CH₂)_(n)alkoxyl group, a branched (CH₂)_(n) alkyl group, a C₃˜C₁₂nephthenicgroup, and a C₃˜C₁₂ cyclic alkoxyl group, wherein 1=n=12, and X is ahalogen; iii) a third substituent being one selected from a groupconsisting of a straight C₁˜C₈ alkyl group with a double-bond, a C₁˜C₈alkoxyl group with a double-bond, a branched C₁˜C₈ alkyl group with adouble-bond and a C₃˜C₈ nephthenic group with a double-bond; and iv) afourth substituent of a C₅˜C₁₂ heterocyclic group.
 2. A compound asclaimed in claim 1, wherein R₁ is an ethyl group.
 3. A compound asclaimed in claim 1, wherein one of the nephthenic group and theheterocyclic group further has at least one of an ortho-substitution, ameta-substitution and a para-substitution, and comprises at least afifth substituent for any of the substitutions being one selected from agroup consisting of an alkyl group with a C₁˜C₃ substituent branch, anamino group, a nitro group, a hydroxyl group and a cyan group, a C₁˜C₅alkyl group, a halogen substituted C₁˜C₅ alkyl group, a C₁˜C₅ alkoxylgroup, a halogen substituted C₁˜C₅ alkoxyl group, a C₁˜C₅ cyclic alkoxylgroup, and a halogen substituted C₁˜C₅ cyclic alkoxyl group.
 4. Acompound as claimed in claim 1, wherein the halogen is one selected froma group consisting of a fluorine, a chlorine, a bromine and an iodine.5. A compound as claimed in claim 1, wherein the second substituent isone selected from a group consisting of a methyl group, an ethyl group,a propyl group, a butyl group, an isobutyl group, a pentyl group, anisopentyl group, a cyclopentyl group, a heptyl group, an isoheptylgroup, a cycloheptyl group, an octyl group, an isooctyl group, acyclooctyl group, a straight alkyl group with a branch substituted by astraight C₁˜C₅ alkyl group, a nephthenic group with a branch substitutedby a straight C₁˜C₅ alkyl group, alkoxyl derivatives of the mentionedalkyl groups, and halogenated derivatives of the mentioned alkyl groups.6. A compound as claimed in claim 1, wherein the third substituent isone selected from a group consisting of a vinyl group, a propenyl group,a butenyl group, an isobutenyl group, a pentenyl group, an isopentenylgroup, a cyclopentenyl group, a hexenyl group, a cyclohexenyl group, aheptenyl group, an cycloheptenyl group, a straight alkyl group with abranch substituted by a straight C₁˜C₃ alkyl group, a nephthenic groupwith a branch substituted by a straight C₁˜C₃ alkyl group, alkoxylderivatives of the mentioned groups, and halogenated derivatives of thementioned groups.
 7. A compound as claimed in claim 1, being used as aneffective component together with an excipient to provide a pharmaceuticcomposition for inhibiting one selected from a group consisting of agrowth of a cancer cell, a disease of cell proliferation, and a growthof cell telomere.
 8. A heteroannelated anthraquinone derivative compoundrepresented by a formula (II):


9. A compound as claimed in claim 8, being used as an effectivecomponent together with an excipient to provide a pharmaceuticcomposition for inhibiting one selected from a group consisting of agrowth of a cancer cell, a disease of cell proliferation, and a growthof cell telomere.
 10. A heteroannelated anthraquinone derivativecompound represented by a formula (III):

wherein either one of R₂ and R₃ is one of: i) a first substituent beingone of a hydryl group and a sulfuryl-group; and ii) a second substituentbeing one selected from a group consisting of a C₁˜C₈ alkyl group, aC₁˜C₈ alkoxyl group, a C₃˜C₈ nephthenic group, and a C₃˜C₈ cyclicalkoxyl group, a straight alkyl group with a branch substitutent, anephthenic group with a branch substitutent by a straight C₁˜C₅ alkylgroup and halogenated derivatives of the mentioned substitent groups.11. A compound as claimed in claim 10, wherein the second substituent isone selected from a group consisting of a methyl group, an ethyl group,a propyl group, a butyl group, an isobutyl group, a pentyl group, anisopentyl group, a cyclopentyl group, a heptyl group, an isoheptylgroup, a cycloheptyl group, an octyl group, an isooctyl group, acyclooctyl group, a phenyl group, a benzyl group, a phenethyl group, astraight alkyl group with a branch substituted by a straight C₁˜C₃ alkylgroup, a nephthenic group with a branch substituted by a straight C₁˜C₃alkyl group, alkoxyl derivatives of the mentioned substituent groups,and halogenated derivatives of the mentioned substituent groups.
 12. Acompound as claimed in claim 10, being used as an effective componenttogether with an excipient to provide a pharmaceutic composition forinhibiting one selected from a group consisting of a growth of a cancercell, a disease of cell proliferation, and a growth of cell telomere.13. A heteroannelated anthraquinone derivative compound represented by aformula (IV):

wherein R4 is one selected from a group consisting of a hydryl group, aC₁˜C₄ alkyl group, a C₁˜C₄ alkoxyl group, a C₁˜C₄ ketone group, astraight alkyl group with a branch substituted by a straight C₁˜C₃ alkylgroup, a halogen substituted C₁˜C₄ alkyl group, and a C₁˜C₄ alkoxylgroup.
 14. A compound as claimed in claim 13, wherein R₄ is a hydrogen.15. A compound as claimed in claim 13, being used as an effectivecomponent together with an excipient to provide a pharmaceuticcomposition for inhibiting one selected from a group consisting of agrowth of a cancer cell, a disease of cell proliferation, and a growthof cell telomere.
 16. A method for manufacturing a compound having aformula (I) as claimed in claim 1, comprising steps of: a) dissolving adiaminoanthraquinone in a dimethylformamide solution for forming asolution A; b) adding and dissolving a chloroacetyl chloride in thesolution A for forming a solution B; c) mixing and reacting the solutionB by a reverse flow method, and then transferring the solution B into anicy water for forming a solution C; d) filtering the solution C forobtaining a precipitate; and e) washing the precipitate by using anethanol for obtaining the compound of the formula (I).
 17. A method formanufacturing a compound having a formula (I) as claimed in claim 1,comprising steps of: a) dissolving a diaminoanthraquinone in adimethylformamide solution for forming a solution A; b) adding anddissolving a reagent in the solution A for forming a solution B, whereinthe reagent is one of a benzaldehyde and a carbon disulfide; c)catalyzing a reaction of the solution B by adding a concentratedsulfuric acid thereinto, and then transferring the solution B into anice water for forming a solution C; d) filtering the solution C forobtaining a precipitate; and e) washing the precipitate by using anethanol for obtaining the compound of the formula (I), wherein when thereagent is the carbon disulfide, a triethylamine is further added intothe solution B before the step c).
 18. A method for manufacturing acompound having a formula (III) as claimed in claim 10, comprising stepsof: a) dissolving a diaminoanthraquinone in an acetone for forming asolution A; b) adding a concentrated sulfuric acid into the solution Afor forming a solution B; c) transferring the solution B into apotassium carbonate column for obtaining a solution C; and d) using amethanol to crystallize the compound of the formula (III) in thesolution C.
 19. A method as claimed in claim 18, wherein the step b) isperformed in a room temperature.
 20. A method for manufacturing acompound having a formula (IV) as claimed in claim 13, comprising stepsof: a) dissolving a diaminoanthraquinone in a dimethylformamide solutionfor forming a solution A; b) adding a glyoxal ethanol solution into thesolution A for forming a solution B; c) reacting the solution B by areverse flow reaction; d) filtering the solution B for obtaining aprecipitate; and e) washing the precipitate by using a hot alcohol and adichloromethane for separating out the compound of the formula (IV).